Gel composition for treatment of common acne comprising a combination of benzoyl perozide and adapalene and/or adapalene salt

ABSTRACT

Dermatological/cosmetic compositions suited for preventing or treating cell differentiation and/or proliferation and/or keratinization disorders, including preventing or treating common acne, comprise, in a physiologically acceptable medium, (i) at least one dispersed retinoid, (ii) dispersed benzoyl peroxide, in free or encapsulated form, and (iii) at least one pH-independent gelling agent, selected from the group consisting of (a) polyacrylamide gelling agents, (b) gelling agents which are acrylic polymers coupled to hydrophobic chains, (c) modified starch gelling agents, and mixture thereof, said composition maintaining good chemical stability of (i) and (ii) without their degradation over time at a temperature of between 4° C. and 40° C.

CROSS-REFERENCE TO EARLIER APPLICATIONS

This application is a continuation of copending U.S. patent applicationSer. No. 10/326,389, filed Dec. 23, 2002 (Attorney Docket No.1034227-000478), which claims benefit of U.S. Provisional ApplicationNo. 60/351,382, filed Jan. 28, 2002, and claims priority under 35 U.S.C.§ 119 of Application No. 01/16747, filed in France on Dec. 21, 2001, allof said applications being hereby expressly incorporated by reference intheir entireties and relied upon.

CROSS-REFERENCE TO RELATED APPLICATION

This application is related to concurrently filed copending U.S.application Ser. No. ______ (Attorney Docket No. 1034227-000897), whichis also a continuation of U.S. patent application Ser. No. 10/326,389and claims the same domestic and foreign priorities.

BACKGROUND OF THE INVENTION Technical Field of the Invention

The invention relates to a composition comprising, in a physiologicallyacceptable medium, at least one retinoid, dispersed benzoyl peroxide andat least one pH-independent gelling agent.

Description of the Prior Art

The use of several classes of active principles is a therapeutic toolthat is frequently employed, especially for treating dermatologicaldisorders.

Specifically, it is known practice in the treatment of dermatitis to usecorticosteroids such as, for example, hydrocortisone, miconazole orbetamethasone valerate, antihistamines (e.g., mizolastine) and/orkeratolytic agents, for instance salicylic acid. Various antifungalagents, for instance allylamine derivatives, triazoles, antibacterialagents or antimicrobial agents such as, for example, antibiotics,quinolones and imidazoles, are also conventionally combined in thetreatment of dermatological diseases. Peroxides, D vitamins andretinoids are also described for the topical treatment of variouspathologies associated with the skin or mucous membranes, in particularacne.

The combination of several local treatments (antibiotics, retinoids,peroxides and zinc) is also used in dermatology to increase the efficacyof the active principles and to reduce their toxicity (Cunliffe W. J.,J. Dermatol. Treat., 2000, 11 (suppl2), pp. 13-14).

The multiple application of various dermatological products may berelatively burdensome and restricting for the patient.

The value in seeking to obtain a novel treatment that is effective ondermatological complaints in a stable composition offering good cosmeticutility, allowing a single application and a utilization that thepatient finds pleasant, may thus be appreciated.

Among this panoply of treatments proposed to a person skilled in theart, there was nothing to encourage him to combine, in the samecomposition, benzoyl peroxide and a retinoid.

However, formulating such a composition poses several problems.

Firstly, the efficacy of benzoyl peroxide is associated with itsdecomposition when it is placed in contact with the skin. Specifically,it is the oxidizing properties of the free radicals produced during thisdecomposition that lead to the desired effect. Thus, in order tomaintain the optimum efficacy of benzoyl peroxide, it is important toprevent its decomposition before use, i.e., during storage.

Benzoyl peroxide is an unstable chemical compound, making it difficultto formulate it in finished products.

The solubility and stability of benzoyl peroxide were studied byChellquist et al., in ethanol, propylene glycol and various mixtures ofpolyethylene glycol 400 (PEG 400) and water (Chellquist E. M. and GormanW. G., Pharm. Res., 1992, Vol 9: 1341-1346). Benzoyl peroxide isparticularly soluble in PEG 400 and ethanol, as shown in the followingtable:

Benzoyl peroxide Solvent solubility (mg/g) PEG 400 39.6 Ethanol 17.9Propylene glycol 2.95 Propylene glycol/water (75:25) 0.36 Glycerol 0.15Water 0.000155

The said document moreover states that the stability of benzoyl peroxideis greatly influenced by the chemical composition of the formulation andby storage temperature. Benzoyl peroxide is extremely reactive anddegrades in solution at low temperature on account of the instability ofits peroxide bond. The authors thus state that benzoyl peroxide insolution degrades more or less quickly in all the solvents studied as afunction of the type of solvent and of its concentration.

The degradation times for benzoyl peroxide in PEG 400 (0.5 mg/g), inethanol and in propylene glycol are, respectively, 1.4, 29 and 53 daysat 40° C.

Such a degradation does not allow the preparation of a product intendedfor sale.

It is moreover known that benzoyl peroxide is more stable in water andpropylene glycol when it is in suspension (i.e., in dispersed form),since it is not degraded after storage for 90 days in these solvents.Thus, in order to limit the problem of rapid instability of benzoylperoxide in solution, it has been found to be advantageous to formulatebenzoyl peroxide in dispersed form. However, this type of formulation isnot entirely satisfactory since degradation of the benzoyl peroxide inthe finished product is still observed.

Another difficulty to be overcome in preparation of a compositioncomprising both benzoyl peroxide and a retinoid is that most retinoidsare particularly sensitive to natural oxidation, to visible light and toultraviolet light, and, since benzoyl peroxide is a strong oxidizingagent, the chemical compatibility of these compounds in the sameformulation poses numerous problems in terms of physical and chemicalstability.

A study of the stability of two retinoids was performed by combining twocommercial products, one containing a retinoid (tretinoin or adapalene)and the second based on benzoyl peroxide (B. Martin et al., Br. J.Dermatol. (1998) 139, (suppl. 52), 8-11). The presence of theformulation based on benzoyl peroxide results in very rapid degradationof the oxidation-sensitive retinoids: it is measured that 50% of thetretinoin is degraded in 2 hours, and 95% in 24 hours. In thecomposition in which the retinoid is adapalene, no degradation of theadapalene was measured over 24 hours. This study confirms that benzoylperoxide becomes degraded and degrades oxidation-sensitive retinoidsover time, gradually releasing benzoic acid into the finished products.In contrast, no indication is given regarding the physical stability ofthe two compositions placed in contact, or regarding the therapeuticactivity that may finally be obtained by combining the two activeprinciples in the same composition. There was no encouragement forcombining these two active agents in order to obtain a stablecomposition of gel type, given that it was commonly known that thepresence of benzoyl peroxide chemically and physically destabilized thistype of composition.

Now, it is clear that the degradation of benzoyl peroxide and retinoidsis not desirable since it impairs the efficacy of the compositioncontaining them.

Moreover, a finished product, in particular when it is a pharmaceuticalor cosmetic composition, must maintain throughout its shelf life precisephysicochemical criteria for ensuring its pharmaceutical or cosmeticquality, respectively. Among these criteria, it is necessary for therheological properties to be maintained. They define the behavior andtexture of the composition during application, but also the activeprinciple's release properties [1998 SFSTP Commission Report] and thehomogeneity of the product when the active principles are presenttherein in dispersed form.

In particular, the formulation of benzoyl peroxide and of a retinoid ingel form is advantageous for topical treatments, such as the treatmentof acne, since it especially avoids a greasy feel being left on theskin.

Another difficulty to be overcome in preparing a composition especiallycomprising benzoyl peroxide, when it is in gel form, is that the gellingagents are destabilized by the benzoic acid released during thedegradation of the benzoyl peroxide.

Specifically, the thickeners most commonly used for formulating thesecompositions with benzoyl peroxide are acrylic acid polymers (Carbomer)and celluloses alone or combined with silicates.

Now, the use of carbomers in compositions of aqueous gel type does notgive good results in terms of chemical stability of the benzoyl peroxideor in terms of rheological stability. As described by Bollinger(Bollinger, Journal of Pharmaceutical Science, 1977, vol 5), it has beenobserved that from 5% to 20% benzoyl peroxide is lost after 2 months at40° C. depending on the neutralizer of the carbomer used. Furthermore,the release of benzoic acid results in depolymerization of thecarbomers, leading to a drop in viscosity which may result in phaseseparation. In other gels consisting of a mixture ofhydroxypropyl-cellulose and aluminum magnesium silicate, a drop inviscosity over time is also observed, resulting in sedimentation of theactive agents as a suspension and heterogeneity of the dispersion in thefinished product.

This instability of benzoyl peroxide gels impairs their efficacy andtheir cosmetic utility.

There is thus still a need for a physically stable gelled compositioncontaining benzoyl peroxide and a retinoid.

SUMMARY OF THE INVENTION

The Applicant has now, surprisingly, produced a composition thatsatisfies this need, which comprises dispersed, free or encapsulatedbenzoyl peroxide, at least one retinoid and a pH-independent gellingagent with good physical stability, i.e., not showing a drop inviscosity over time and at temperatures of between 4 and 40° C., andmaintaining good chemical stability of the two active agents (benzoylperoxide and retinoid), i.e., no degradation of the active agents overtime and at temperature of between 4 and 40° C. is observed. TheApplicant has also discovered, surprisingly, that total dispersion ofthe active principles can be obtained by following a particularpreparation process. This preparation process performed without heatmakes it possible to obtain an optimum particle size and uniformdispersion of the two active agents in the composition, while at thesame time ensuring the physical stability of the product.

The invention thus relates to a composition comprising, in aphysiologically acceptable medium, at least one retinoid, dispersedbenzoyl peroxide and at least one pH-independent gelling agent.

DETAILED DESCRIPTION OF BEST MODE AND SPECIFIC/PREFERRED EMBODIMENTS OFTHE INVENTION

The composition according to the invention is preferably in the form ofan aqueous gel.

The term “aqueous gel” means a composition containing, in an aqueousphase, a viscoelastic mass formed from colloidal suspensions (gellingagent).

The expression “pH-independent gelling agent” means a gelling agentcapable of giving the composition a viscosity that is sufficient to keepthe retinoid and the benzoyl peroxide in suspension, even under theinfluence of a variation in pH caused by the release of benzoic acid bythe benzoyl peroxide.

Non-limiting examples that may be mentioned include the gelling agentsof the polyacrylamide family, such as the mixture of sodiumacryloyldimethyltaurate copolymer/isohexadecane/polysorbate 80 soldunder the name Simulgel 600 by the company SEPPIC, the mixture ofpolyacrylamide/isoparaffin C13-14/laureth-7 such as, for example, theproduct sold under the name Sepigel 305 by the company SEPPIC, thefamily of acrylic polymers coupled to hydrophobic chains, such as thePEG-150/decyl/SMDI copolymer sold under the name Aculyn 44(polycondensate comprising at least, as components, a polyethyleneglycol containing 150 or 180 mol of ethylene oxide, decyl alcohol andmethylenebis (4-cyclohexyl isocyanate) (SMDI), at 35% by weight in amixture of propylene glycol (39%) and water (26%)), the family ofmodified starches, such as the modified potato starch sold under thename methylenebis (4-cyclohexyl isocyanate) (SMDI), Structure Solanace,or mixtures thereof.

The preferred gelling agents are derived from the polyacrylamide family,such as Simulgel 600 or Sepigel 305, or mixtures thereof.

The gelling agent as described above may be used in preferentialconcentrations ranging from 0.1% to 15% and more preferably ranging from0.5% to 5%.

The composition according to the invention contains at least oneretinoid.

The term “retinoid” means any compound that binds to the RAR and/or RXRreceptors.

Preferably, the retinoid is a compound chosen from the family ofbenzonaphthalene retinoids as described in patent application EP 0 199636. In particular, adapalene and also precursors and/or derivativesthereof will be preferred.

The expression “retinoid precursors” means the immediate biologicalprecursors or substrates thereof, and also the chemical precursorsthereof.

The expression “retinoid derivative” means both their metabolicderivatives and their chemical derivatives.

Other retinoids may be chosen from those described in the followingpatents or patent applications: U.S. Pat. No. 4,666,941, U.S. Pat. No.4,581,380, EP 0 210 929, 15 EP 0 232 199, EP 0 260 162, EP 0 292 348, EP0 325 540, EP 0 359 621, EP 0 409 728, EP 0 409 740, EP 0 552 282, EP 0584 191, EP 0 514 264, EP 0 514 269, EP 0 661 260, EP 0 661 258, EP 0658 553, EP 0 679 628, EP 0 679 631, EP 0 679 630, EP 0 708 100, EP 0709 382, EP 0 722 928, EP 0 728 739, EP 0 732 328, EP 0 740 937, EP 0776 885, EP 0 776 881, EP 0 823 903, EP 0 832 057, EP 0 832 081, EP 0816 352, EP 0 826 657, EP 0 874 626, EP 0 934 295, EP 0 915 823, EP 0882 033, EP 0 850 909, EP 0 879 814, EP 0 952 974, EP 0 905 118, EP 0947 496, WO 98/56783, WO 99/10322, WO 99/50239, WO 99/65872.

Needless to say, the amount of the two active agents, benzoyl peroxideand retinoid, in the composition according to the invention will dependon the combination chosen and thus particularly on the retinoid underconsideration and the quality of the desired treatment.

The preferred retinoid concentrations are between 0.0001% and 20% byweight relative to the total weight of the composition.

Benzoyl peroxide may also be used in free form or in an encapsulatedform in a form adsorbed onto, or absorbed in, any porous support. It maybe, for example, benzoyl peroxide encapsulated in a polymer systemconsisting of porous microspheres, such as, for example, microspongessold under the name Microsponges P009A Benzoyl peroxide by the companyAdvanced Polymer System.

To give an order of magnitude, the composition according to theinvention advantageously comprises between 0.0001% and 20% by weight ofbenzoyl peroxide and between 0.0001% and 20% by weight of retinoidrelative to the total weight of the composition, and preferably,respectively, between 0.025% and 10% by weight of benzoyl peroxide andbetween 0.001% and 10% by weight of retinoid relative to the totalweight of the composition.

For example, in compositions for treating acne, the benzoyl peroxide ispreferably used at concentrations ranging from 2% to 10% by weight andmore particularly from 2.5% to 5% by weight, relative to the totalweight of the composition. As regards the retinoid, it is used in thistype of composition at concentrations generally ranging from 0.05% to 1%by weight relative to the total weight of the composition.

Advantageously, the particle size of the retinoid and of the benzoylperoxide is such that at least 80% in numerical terms of the particles,and preferably at least 90% in numerical terms of the particles, have adiameter of less than 25 μm and at least 99% in numerical terms of theparticles have a diameter of less than 100 μm.

According to the invention, the gel containing benzoyl peroxide and aretinoid advantageously comprises at least water and may also comprise apro-penetrating agent and/or a liquid wetting surfactant.

The compositions of the invention may contain one or morepro-penetrating agents in preferential concentrations ranging from 0% to20% and more preferably ranging from 2% to 6% by weight, relative to thetotal weight of the composition. They should generally not dissolve theactive agents at the percentage used, should not cause any exothermicreactions harmful to the benzoyl peroxide, should aid in thesatisfactory dispersion of the active agents, and should haveantifoaming properties. Among the pro-penetrating agents preferablyused, without this list being limiting, are compounds such as propyleneglycol, dipropylene glycol, propylene glycol dipelargonate, lauroglycoland ethoxydiglycol.

The pro-penetrating agent that is particularly preferred is propyleneglycol.

Advantageously, the compositions according to the invention may alsocontain one or more liquid wetting surfactants in preferentialconcentrations ranging from 0% to 10% and more preferably ranging from0.1% to 2%. The wetting power is the tendency of a liquid to spread overa surface.

They are preferably surfactants with an HLB (Hydrophilic-LipophilicBalance) value from 7 to 9, or nonionic surfactants such aspolyoxyethylenated and/or polyoxypropylenated copolymers. They should beliquid so as to be readily incorporated into the composition without itbeing necessary to heat them.

Among the wetting agents that are preferably used, without this listbeing limiting, are compounds of the Poloxamer family and moreparticularly Poloxamer 124 and/or Poloxamer 182.

The liquid wetting surfactant that is particularly preferred isPoloxamer 124.

The composition may also comprise any additive usually used in thecosmetics or pharmaceutical field, such as sequestering agents,antioxidants, sunscreens, preserving agents, fillers, electrolytes,humectants, colorants, common mineral or organic acids or bases,fragrances, essential oils, cosmetic active agents, moisturizers,vitamins, essential fatty acids, sphingolipids, self-tanning compoundssuch as DHA, and calmants and protective agents for the skin such asallantoin. Needless to say, a person skilled in the art will take careto select this or these optional additional compound(s), and/or theamount thereof, such that the advantageous properties of the compositionaccording to the invention are not, or are not substantially, adverselyaffected.

These additives may be present in the composition in a proportion offrom 0% to 20% by weight relative to the total weight of thecomposition.

Examples of sequestering agents that may be mentioned includeethylenediaminetetraacetic acid (EDTA), and also derivatives or saltsthereof, dihydroxyethylglycine, citric acid and tartaric acid, ormixtures thereof.

Examples of preserving agents that may be mentioned include benzalkoniumchloride, phenoxy-ethanol, benzyl alcohol, diazolidinylurea andparabens, or mixtures thereof.

Examples of humectants that may be mentioned include glycerol andsorbitol.

In particular, the invention also relates to a pharmaceutical orcosmetic composition for topical application to the skin, theinteguments or mucous membranes, in the form of an aqueous gel,characterized in that it contains, in a physiologically acceptablemedium that is compatible with topical application to the skin, theinteguments or mucous membranes, an active phase comprising (expressedin percentages by weight):

-   0% to 90%, preferably 5% to 25% and especially 10% to 20%, of water;-   0% to 10%, preferably 0 to 2% and especially 0% to 0.5%, of liquid    wetting surfactant;-   0% to 20%, preferably 0% to 10% and especially 2% to 5%, of    pro-penetrating agent;-   0.0001% to 20% and preferably 0.025% to 10%, of benzoyl peroxide;-   0.0001% to 20% and preferably 0.001% to 10%, of retinoid; and-   an aqueous phase comprising a pH-independent gelling agent, and    water.

The aqueous phase of the emulsion according to the invention maycomprise water, a floral water such as cornflower water, or naturalmineral or spring water chosen, for example, from eau de Vittel, watersof the Vichy basin, eau d'Uriage, eau de la Roche Posay, eau de laBourboule, eau d'Enghien-les-Bains, eau de Saint Gervais-les-Bains, eaude Néris-les-Bains, eau d'Allevard-les-Bains, eau de Digne, eau deMaizières, eau de Neyrac-les-Bains, eau de Lons-le-Saunier, les EauxBonnes, eau de Rochefort, eau de Saint Christau, eau des Fumades, eau deTercis-les-bains, eau d'Avène or eau d'Aix les Bains.

The said aqueous phase may be present in a content of between 10% and90% by weight and preferably between 20% and 80% by weight, relative tothe total weight of the composition.

A composition that is preferred according to the invention comprises inwater:

-   2.50% benzoyl peroxide,-   0.10% adapalene,-   0.10% disodium EDTA,-   4.00% glycerol,-   4.00% propylene glycol,-   0.05% sodium docusate,-   0.20% Poloxamer 124,-   4.00% sodium acryloyldimethyltaurate copolymer & isohexadecane &    polysorbate 80,-   sodium hydroxide, qs pH 5.

A subject of the present invention is also the composition as describedabove, as a medicinal product.

The invention also relates to the use of the novel composition asdescribed above in cosmetics and dermatology.

A subject of the invention is also a process for preparing a compositionof aqueous gel type, comprising the production of an active phase, of anaqueous phase and of a gelling phase, at room temperature (RT), i.e.,between 20 and 25° C., and successively comprising the following steps:

-   a) the preparation of an aqueous phase comprising water and    optionally a chelating agent and/or a pro-penetrating agent and/or a    humectant;-   b) the preparation of an active phase comprising the mixture in    water of the retinoid, of benzoyl peroxide and, optionally, of a    liquid wetting surfactant and/or of a pro-penetrating agent, with    stirring;-   c) the introduction of the active phase into the aqueous phase, with    stirring; and-   d) the introduction of the gelling agent into the mixture obtained    from step c), with stirring.

In one embodiment, the process for preparing the aqueous gelcomposition, comprising the production of an active phase, of an aqueousphase and of a gelling phase, at room temperature, successivelycomprises the following steps:

-   a) the preparation of an aqueous phase comprising water and    optionally a chelating agent and/or a pro-penetrating agent and/or a    humectant;-   b) the preparation of two active agents, one comprising the mixture    in water of the retinoid, the other comprising the mixture in water    of benzoyl peroxide and, optionally, of a liquid wetting surfactant    and/or of a pro-penetrating agent, with stirring;-   c) the introduction of the active phases into the aqueous phase,    with stirring; and-   d) the introduction of the gelling agent into the mixture obtained    from step c), with stirring.

The aqueous gel prepared according to one of these procedures was foundto provide many advantages over the preparation of other already-knownaqueous gels, especially since it is simpler, and, since theincorporation of the gelling agent into the end of the process makes itpossible to obtain better dispersion of the particles by enclosure,these gels may also be film-forming and may thus limit perspiration. Atleast 80% in numerical terms of the particles and preferably at least90% in numerical terms of the particles have a diameter of less than 25μm and at least 99% in numerical terms of the particles have a diameterof less than 100 μm in the composition.

On account of the keratolytic, bactericidal and antiinflammatoryactivity of benzoyl peroxide and the pronounced activity of retinoids inthe fields of cell differentiation and proliferation, the compositionsof the invention are particularly suitable in the following therapeuticfields:

-   1) for treating dermatological complaints associated with a    keratinization disorder relating to differentiation and    proliferation, especially for treating common acne, comedones,    polymorphonuclear leukocytes, acne rosacea, nodulocystic acne, acne    conglobata, senile acne, secondary acnes such as solar acne,    medication-related acne or occupational acne, and suppurative    hydradenitis,-   2) for treating other types of keratinization disorder, especially    ichtyosis, ichtyosiform conditions, Darier's disease, palmoplantar    keratoderma, leukoplakia and leukoplakiform conditions, and    cutaneous or mucous (buccal) lichen,-   3) for treating other dermatological complaints associated with a    keratinization disorder with an inflammatory and/or immunoallergic    component, and especially all forms of psoriasis, whether cutaneous,    mucous or ungual psoriasis, and even psoriatic rheumatism, or    cutaneous atopy, such as eczema, or respiratory atopy, or even    gingival hypertrophy; the compounds may also be used in certain    inflammatory complaints not exhibiting a keratinization disorder,    such as folliculitis,-   4) for treating all dermal or epidermal proliferations, whether    benign or malignant, and whether of viral origin or otherwise, such    as common warts, flat warts, molluscum contagiosum and verruciform    epidermodysplasia, oral or florid papillomatoses and proliferations    that may be induced by ultraviolet radiation, especially in the case    of actinic keratosis,-   5) for repairing or combating aging of the skin, whether photo    induced or chronological aging, or for reducing pigmentation, or any    pathology associated with chronological or actinic aging,-   6) for preventively or curatively treating cicatrization disorders    and skin ulcers, for preventing or repairing stretch marks, or for    promoting cicatrization,-   7) for combating sebaceous function disorders such as the    hyperseborrhoea of acne or simple seborrhoea,-   8) in the treatment of any complaint of fungal origin on the skin,    such as tinea pedis and tinea versicolor,-   9) in the treatment of dermatological complaints with an    immunological component,-   10) in the treatment of skin disorders caused by exposure to UV    rays, and-   11) in the treatment of dermatological complaints associated with    inflammation or infection of the tissues surrounding the hair    follicles, caused especially by microbial colonization or infection,    especially impetigo, seborrhoeic dermatitis, folliculitis or sycosis    barbae, or involving any other bacterial or fungal agent.

The compositions according to the invention are particularly suitablefor preventively or curatively treating common acne.

A subject of the invention also relates to the manufacture of apharmaceutical preparation for preventing or treating dermatologicalcomplaints associated with cell differentiation and/or proliferationdisorders and/or keratinization disorders, and also to the manufactureof a pharmaceutical preparation for preventing or treating common acne.

The compositions according to the invention also find an application incosmetics, in particular for treating acne-prone skin, for regrowth ofthe hair, for preventing hair loss, for combating the greasy appearanceof the skin or the hair, in protecting against the harmful effects ofsunlight or in the treatment of physiologically dry skin, or forpreventing and/or combating photo induced or chronological aging.

The compositions according to the invention also find an application inbody and hair hygiene.

The present invention thus relates also to the cosmetic use of acomposition according to the invention for treating acne-prone skin, forregrowth of the hair or for preventing hair loss, for combating thegreasy appearance of the skin or the hair, in protecting against harmfuleffects of sunlight or in treating physiologically dry skin, or forpreventing and/or controlling photo induced or chronological aging.

The formulation examples below illustrate the compositions according tothe invention without, however, limiting its scope. Examples ofprocesses for preparing the compositions according to the invention,mentioned in a non-limiting manner, and also examples illustrating thephysical and chemical stability of the compositions, are also described.

I. FORMULATION EXAMPLES

In the compositions below (Examples 1 to 5), the proportions of thevarious constituents are expressed as percentages by weight relative tothe total weight of the composition.

Example 1

Phase Components % Active BENZOYL PEROXIDE 5.00% ADAPALENE 0.10%DIPROPYLENE GLYCOL 4.00% PURIFIED WATER   10% POLOXAMER 182 0.20%Aqueous PURIFIED WATER qs 100% SILICA 0.02% GLYCEROL 2.00% MICROSPONGES4.00% Gelling POLYACRYLAMIDE (and) C13-14 ISOPARAFFIN 3.50% (and)LAURETH-7

Example 2

Phase Components % Active BENZOYL PEROXIDE   5% ADAPALENE 0.10% PURIFIEDWATER 10.00%  PROPYLENE GLYCOL 2.00% POLOXAMER 124 0.20% AqueousPURIFIED WATER qs 100% DISODIUM EDTA 0.10% GLYCEROL 4.00% PROPYLENEGLYCOL 2.00% SODIUM DOCUSATE 0.05% Gelling SODIUMACRYLOYLDIMETHYLTAURATE 4.00% COPOLYMER & ISOHEXADECANE & POLYSORBATE 80

Example 3

Phase Components % Active BENZOYL PEROXIDE  2.5% ADAPALENE 0.10%PURIFIED WATER 10.00%  PROPYLENE GLYCOL 2.00% POLOXAMER 124 0.20%Aqueous PURIFIED WATER qs 100% DISODIUM EDTA 0.10% GLYCEROL 4.00%PROPYLENE GLYCOL 2.00% SODIUM DOCUSATE 0.05% Gelling SODIUM 4.00%ACRYLOYLDIMETHYLTAURATE COPOLYMER & ISOHEXADECANE & POLYSORBATE 80 pHmodifier SODIUM HYDROXIDE qs pH 5.00

Example 4

Phase Components % Active BENZOYL PEROXIDE 5.00% ADAPALENE 0.10%PURIFIED WATER 10.00%  PROPYLENE GLYCOL 2.00% POLOXAMER 124 0.20%Aqueous PURIFIED WATER qs 100% DISODIUM EDTA 0.10% GLYCEROL 4.00%PROPYLENE GLYCOL 2.00% SODIUM C14-16 OLEFIN 0.05% SULFONATE GellingPEG-150/decyl/SMDI copolymer  3.5%

Example 5

Phase Components % Active 1 BENZOYL PEROXIDE  2.5% PURIFIED WATER20.00%  PROPYLENE GLYCOL 1.00% POLOXAMER 124 0.10% Phase ADAPALENE 0.10%Active 2 PROPYLENE GLYCOL 1.00% POLOXAMER 124 0.10% Aqueous PURIFIEDWATER qs 100% DISODIUM EDTA 0.10% GLYCEROL 4.00% PROPYLENE GLYCOL 2.00%SODIUM DOCUSATE 0.05% Gelling SODIUM 4.00% ACRYLOYLDIMETHYLTAURATECOPOLYMER & ISOHEXADECANE & POLYSORBATE 80 pH modifier SODIUM HYDROXIDEqs pH 5.00

II. EXAMPLES OF A PREPARATION PROCESS Example 6

The examples of a preparation process are given in a non-limitingmanner. The preparation presented is that of the composition that is thesubject of Example 3:

PROCEDURE PARAMETERS Introduce the following into T°: RT ° C. beaker(Phase 1): STIRRER: Rayneri purified water PADDLE: deflocculatingdisodium EDTA STIRRING: 350 rmp glycerol TIME: 10 min Introduce thefollowing into a T°: RT ° C. related beaker: STIRRER: stirring platepropylene glycol PADDLE: magnetic br sodium docusate TURBOMIXER: N.A.Place under magnetic stirring TIME: 45 min until the sodium docusate isfully dissolved Active phase: Introduce the T°: RT ° C. following into arelated beaker STIRRER: disperser of suitable size: PADDLE: Polytronpropylene glycol (PG) STIRRING: 9000 rpm Poloxamer 124 TIME: 30 minpurified water benzoyl peroxide adapalene Stir using a Polytron stirreruntil the active agents are fully dispersed, in a bath of cold water toavoid overheating of the active agents. When the mixture of sodium T°:RT ° C. docusate + PG is fully dissolved, STIRRER: Rayneri incorporateit into Phase 1. PADDLE: deflocculating Next, add the active phase.STIRRING: 400-500 rpm Stir with a Rayneri stirrer until TIME: 20 min ahomogeneous mixture is obtained. Finally, add the following: T°: RT ° C.Simulgel 600 STIRRER: Rayneri Stir with a Rayneri stirrer for PADDLE:deflocculating the time required for good STIRRING: 1000-1200 rpmhomogeneity of the finished TIME: 25 min product. Neutralization: Adjustthe pH to T°: RT ° C. 5.00 ± 0.3 with: STIRRER: Rayneri 10% sodiumhydroxide, qs PADDLE: deflocculating STIRRING: 1000-1200 rpm TIME: 25min

The preparation given is that of the composition that is the subject ofExample 5:

PROCEDURE PARAMETERS Introduce the following into a T°: RT ° C. beaker:STIRRER: Rayneri purified water PADDLE: deflocculating disodium EDTASTIRRING: 350 rpm sodium docusate TIME: 50 min propylene glycol Placeunder magnetic stirring until the sodium docusate is fully dissolvedNext, introduce the following: T°: RT ° C. glycerol STIRRER: stirringplate PADDLE: deflocculating STIRRING: 350 rpm TIME: 5 min Active phase1: Introduce the T°: RT + cold water bath following into a relatedbeaker PADDLE: Ultra-Turrax of suitable size: STIRRING: 13500 rpmpropylene glycol (PG) TIME: 30 min Poloxamer 124 purified water benzoylperoxide Stir until the active agent is fully dispersed, in a cold waterbath to avoid overheating. Active phase 2: Introduce the T°: RT + coldwater bath following into a related beaker PADDLE: Ultra-Turrax ofsuitable size: STIRRING: 9500 rpm propylene glycol (PG) TIME: 15 minPoloxamer 124 adapalene. Incorporate the active phase 2 T°: RT ° C. intothe aqueous phase. STIRRER: Rayneri Next, add the active phase 1.PADDLE: deflocculating Stir using a Rayneri stirrer STIRRING: 300 rpmuntil a homogeneous mixture is TIME: 20 min obtained Finally, add thefollowing: T°: RT ° C. Simulgel 600 STIRRER: Rayneri Stir using aRayneri stirrer for the PADDLE: deflocculating time required for goodhomogeneity STIRRING: 680 rpm of the finished product TIME: 35 minNeutralization: Adjust the pH to T°: RT ° C. 5.00 ± 0.3 with: STIRRER:Rayneri 10% sodium hydroxide, qs PADDLE: deflocculating STIRRING: 680rpm TIME: 25 min

III. STABILITY STUDY Example 6

Physical stability of the composition by measuring the flow threshold(in Pa·s⁻¹)

The tests performed are viscosity measurements for plotting curves knownas rheograms, which make it possible, for a given rate gradient γ, tomeasure a shear stress τ, and for a given shear stress τ, to measure arate gradient γ (“Initiation à la rhéologie” [Introduction to rheology]Gouarraze-Grossiord 1991; “La viscositeé et sa mesure dans lespharmacopées” [Viscosity and its measurement in pharmacopoeias]; L.Molle, Journal Pharma Belg. 1975, 30, 5-6, 597-619).

The term “yield value” means the force required (minimum shear stress)to overcome the cohesion forces of Van der Waals type and to bring aboutflow.

The yield value (τ0) is extrapolated either visually (y-axis at theorigin of the rheograms) or by calculation (application of mathematicalmodels).

Composition of the Gels Used: Aqueous Gel Based Carbomer

Constituents % PURIFIED WATER qs 100% DISODIUM EDTA 0.10 SODIUM DOCUSATE0.05 SILICA (AEROSIL 200) 0.02 CARBOMER (CARBOPOL 980) 0.85 GLYCEROL4.00 PROPYLENE GLYCOL 4.00 POLOXAMER 124 0.20 BENZOYL PEROXIDE qs 2.5%BPO MICROSPONGES ADAPALENE 0.10 10% SODIUM HYDROXIDE 2.00 qs pH 5

Aqueous Gel Based on Hydroxypropylcellulose

Constituents % PURIFIED WATER qs 100% DISODIUM EDTA 0.10 SILICA (AEROSIL200) 0.02 GLYCEROL 4.00 CLAY (VEEGUM K) 2.00 XANTHAN GUM (KELTROL T) 0.5HYDROXYPROPYLCELLULOSE 1.5 (NATROSOL HHX) PROPYLENE GLYCOL 4.0 SODIUMDOCUSATE 0.05 POLOXAMER 124 0.2 BENZOYL PEROXIDE MICROSPONGES qs 2.5%BPO ADAPALENE 0.10

Aqueous gel based on hydroxypropyl- Example 2 in cellulose andaccordance Aqueous gel aluminum with the based on magnesium inventioncarbomer silicate Temperature RT T40° C. RT T40° C. RT T40° C. T initial137 / 111 / 170 T 1 month 139 137 135 111 183 93 T 2 months 147 121 / /158 65 T 3 months 149 127 100  76 147 34 RT: room temperature T40° C.:storage at 40° C.

The yield value of the composition according to the invention is stableover time and with temperature, unlike the other two examples of aqueousgel, whose viscosity falls rapidly over time, both at room temperatureand at 40° C. These results demonstrate the very good physical stabilityof the composition according to the invention over time, unlike thestandard compositions of aqueous gels.

Example 7

Stability of Benzoyl Peroxide Over Time and as a Function of the StorageTemperature by Measuring the Amount of Benzoyl Peroxide in theComposition (in Percentages)

The percentages of benzoyl peroxide (BPO) presented in the table belowwere obtained by measuring the benzoyl peroxide concentration byiodometry. A suitable amount of composition is first dissolved inpurified water and then in acetonitrile, and subjected to the action ofa potassium iodide solution. When the potassium iodide is added, a colorchange from white to brown takes place, indicating the presence ofbenzoyl peroxide in the composition. The iodine released is titratedusing 0.1N sodium thiosulphate solution:

I ₂+2N₂S₂O₃→2NaI+Na₂S₄O₆

The percentages of benzoyl peroxide given in the table below correspondto the percentage of benzoyl peroxide measured in the product relativeto the theoretical amount introduced.

Aqueous gel based on hydroxypropyl- cellulose and Example 2 in Aqueousgel aluminum accordance with based on magnesium the invention carbomersilicate Temperature RT T40° C. RT T40° C. RT T40° C. % BPO at T 100   /94.3 / 101.7 initial % BPO at T Not 102.5 95.7 90.3 / 94.9 1 monthperformed % BPO at T Not  99.1 94.3 85.5 / 87.3 2 months performed % BPOat T 102.4 100.3 94 78.3  99.7 85.8 3 months

In the composition of Example 2, the percentage of benzoyl peroxide overtime remains stable and equivalent to 100% both at room temperature andat 40° C. The benzoyl peroxide present in the other two examples ofprior-art aqueous gels degrades significantly over time. After 3 months,a loss of benzoyl peroxide that is up to 6% at room temperature and atleast 14% at T40° C. may be observed. These results demonstrate that thecompositions according to the invention allow very good stability ofbenzoyl peroxide over time, even at 40° C., unlike standardcompositions.

1-34. (canceled)
 35. A physiologically acceptable aqueous gel composition for treatment of common acne comprising: 0.05% to 1% adapalene and/or at least one pharmaceutically acceptable salt thereof, 2.5% to 5% dispersed benzoyl peroxide; and 2 to 5% of at least one pH-independent gelling agent of the polyacrylamide family, said percentages being based on the weight of the total aqueous gel composition for treatment of common acne.
 36. The physiologically acceptable aqueous gel composition of claim 35 comprising: 0.15% adapalene and/or at least one pharmaceutically acceptable salt thereof, and 3% dispersed benzoyl peroxide said percentages being based on the weight of the total aqueous gel composition for treatment of common acne.
 37. The physiologically acceptable aqueous gel composition of claim 35 comprising: 0.3% adapalene and/or at least one pharmaceutically acceptable salt thereof, and 2.5% dispersed benzoyl peroxide said percentages being based on the weight of the total aqueous gel composition for treatment of common acne.
 38. The physiologically acceptable aqueous gel composition of claim 35 further comprising at least one additive used in the cosmetics or pharmaceutical field chosen from corticosteroids, antihistamines, antifungal agents, and antibacterial agents, wherein the at least one additive is present in a combined amount ranging from 0.01 to 20% based on the weight of the total aqueous gel composition for treatment of common acne.
 39. The physiologically acceptable aqueous gel composition of claim 35, wherein the at least one pH-independent gelling agent of the polyacrylamide family is chosen from polyacrylamide/C13-14 isoparaffin/laureth-7 gelling agent and acrylamide sodium acryloyldimethyltaurate copolymer/isohexadecane/polysorbate 80 gelling agent.
 40. A method for treating common acne comprising administering, to a subject in need thereof, a physiologically acceptable aqueous gel composition for treatment of common acne comprising: 0.05% to 1% adapalene and/or at least one pharmaceutically acceptable salt thereof, 2.5% to 5% dispersed benzoyl peroxide; and 2% to 5% of at least one pH-independent gelling agent of the polyacrylamide family, said percentages being based on the weight of the total aqueous gel composition for treatment of common acne.
 41. The method of claim 40, wherein the physiologically acceptable aqueous gel composition comprises: 0.15% adapalene and/or at least one pharmaceutically acceptable salt thereof, and 3% dispersed benzoyl peroxide said percentages being based on the weight of the total aqueous gel composition for treatment of common acne.
 42. The method of claim 40, wherein the physiologically acceptable aqueous gel composition comprises: 0.3% adapalene and/or at least one pharmaceutically acceptable salt thereof, and 2.5% dispersed benzoyl peroxide said percentages being based on the weight of the total aqueous gel composition for treatment of common acne.
 43. The method of claim 40, wherein the physiologically acceptable aqueous gel composition further comprises at least one additive used in the cosmetics or pharmaceutical field chosen from corticosteroids, antihistamines, antifungal agents, and antibacterial agents, wherein the at least one additive is present in a combined amount ranging from 0.01 to 20% based on the weight of the total aqueous gel composition for treatment of common acne.
 44. The method of claim 40, wherein the at least one pH-independent gelling agent of the polyacrylamide family is chosen from polyacrylamide/C13-14 isoparaffin/laureth-7 gelling agent and acrylamide sodium acryloyldimethyltaurate copolymer/isohexadecane/polysorbate 80 gelling agent.
 45. A product for treatment of common acne comprising: a container; and a physiologically acceptable aqueous gel composition for treatment of common acne comprising: 0.05% to 1% adapalene and/or at least one pharmaceutically acceptable salt thereof; 2.5% to 5% dispersed benzoyl peroxide; and 2% to 5% of at least one pH-independent gelling agent of the polyacrylamide family, said percentages being based on the weight of the total aqueous gel composition for treatment of common acne, wherein the container contains the aqueous gel composition for treatment of common acne.
 46. The product of claim 45, wherein the physiologically acceptable aqueous gel composition comprises anti-acne actives consisting of: 0.15% adapalene and/or at least one pharmaceutically acceptable salt thereof, and 3% dispersed benzoyl peroxide said percentages being based on the weight of the total aqueous gel composition for treatment of common acne.
 47. The product of claim 45, wherein physiologically acceptable aqueous gel composition comprises anti-acne actives consisting of: 0.3% adapalene and/or at least one pharmaceutically acceptable salt thereof, and 2.5% dispersed benzoyl peroxide said percentages being based on the weight of the total aqueous gel composition for treatment of common acne.
 48. The product of claim 45, wherein the physiologically acceptable aqueous gel composition further comprises at least one additive used in the cosmetics or pharmaceutical field chosen from corticosteroids, antihistamines, antifungal agents, and antibacterial agents, wherein the at least one additive is present in a combined amount ranging from 0.01 to 20%, based on the weight of the total aqueous gel composition for treatment of common acne.
 49. The product of claim 45, wherein the at least one pH-independent gelling agent of the polyacrylamide family is chosen from polyacrylamide/C13-14 isoparaffin/laureth-7 gelling agent and acrylamide sodium acryloyldimethyltaurate copolymer/isohexadecane/polysorbate 80 gelling agent. 